Benzenesulfonamidopyrimidines

ABSTRACT

NEW SULFONAMIDOPYRIMIDINES WITH HYPOGLYCEMIC PROPERTIES HAVING THE FORMULA   1-((X-QUINOL-8-YL)-CO-NH-Y-),2-R,4-((4-R&#34;,5-R&#39;&#39;-PYRIMIDIN-   2-YL)-NH-SO2-)BENZENE   IN WHICH X REPRESENTS HYDROGEN, CHLORINE, BROMINE, METHYL, METHOXY Y REPRESENTS -CH(CH3)-CH2-, OR, PREFERABLY,   -CH2-CH2-   R REPRESENTS HYDROGEN OR, TOGETHER WITH Y, A BRIDGE OF 3 OR 4 CARBON ATOMS, R&#39;&#39; REPRESENTS ALKYL, CYCLOALKYL, CYCLOALKYLALKYL, ARYL, ARALKYL, ALKOXY, CYCLOALKOXY, ALKOXYALKYL, ALKOXYALKOXY, ALKYLMERCAPTO, ALKYLMERCAPTOALKYL, THE ALKLY CONTAINING, IN ANY CASE FROM 1 TO 4 CARBON ATOMS AND THE CYCLOALKYL, IN ANY CASE, 5 TO 8 CARBON ATOMS, R&#34; REPRESENTS HYDROGEN, LOWER ALKYL, R&#34; AND R&#39;&#39; TOGETHER BEING ABLE TO FORM A RING OF FROM 3 TO 5 METHYL GROUPS, AND PHYSIOLOGICALLY TOLERABLE SALTS THEREOF AND PROCESSES FOR THEIR PREPARATION.

United States Patent Office 3,816,424 Patented June 11, 1974 3,816,424BENZENESULFONAMIDOPYRIMIDENES Rudi Weyer, Frankfurt am Main, WalterAumuller, Kelk heim, Taunus, Roland Schweitzer, Falkensteiu, Taunus,Helmut Weber, Frankfurt am Main, and Manfred Hubner, Ludwigshafen amRhine, Germany, assignors to Farbwerke Hoechst Aktiengesellschaftvormals Meister Lucius & Bruniug, Frankfurt am Main, Germany No Drawing.Filed Feb. 15, 1972, Ser. No. 226,530 Int. Cl. C07d 57/00 Claimspriority, application Germany, Feb. 17, 1971, P 21 07 557.0 US. Cl.260-256.5 R Claims ABSTRACT OF THE DISCLOSURE New sulfonamidopyrimidineswith hypoglycemic properties having the formula X represents hydrogen,chlorine, bromine, methyl, me-

thoxy Y represents CH(CH )CH or, preferably,

R represents hydrogen or, together with Y, a bridge of 3 or 4 carbonatoms,

represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, alkoxy,cycloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylmercapto,alkylmercaptoalkyl, the alkyl containing, in any case from 1 to 4 carbonatoms and the cycloalkyl, in any case, 5 to 8 carbon atoms, R"represents hydrogen, lower alkyl, R" and R together being able to form aring of from 3 to 5 methyl groups,

and physiologically tolerable salts thereof and processes for theirpreparation.

The present invention relates to sulfonamidopyrimidines of the formulawhich have inthe free form or in the form of their salts hypoglycemicproperties and are distinguished by a strong and long lastinghypoglycemic action.

In the above formula X represents hydrogen, chlorine, bromine, methyl,me-

thoxy Y represents --CH(CH )CH or, preferably,

-CH CH R represents hydrogen or, together with Y, a bridge of 3 or 4carbon atoms,

R represents alkyl, cycloalkyl, cycloalkylalkyl, aryl,

aralkyl, alkoxy, cycoalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylmercapto,alkylmercaptoalkyl, the alkyl containing, in any case from 1 to 4 carbonatoms and the cycloalkyl, in any case, 5 to 8 carbon atoms,

R" represents hydrogen, lower alkyl, R" and R' together being able toform a ring of from 3 to 5 methylene groups.

The present invention furthermore provides processes for the manufactureof these benzenesulfonamidopyrimidines which comprise (a) reactingcompounds of formula in which X, Y and R are defined as above and n is0, 1 or 2, with Z-aminopyrimidines of the formula in which R and R" aredefined as above, and optionally oxydizing the compounds obtained toyield sulfonamides, or (b) reacting benzenesulfonylguanidines of theformula in which X, Y and R are defined as above with compounds of theformula in which X, Y and R are defined as above, with a pyrimidene ofthe formula 3 in which R" and R' are defined as above and T represents areactive ester group, the group NH-NO NHCN or a low moleculartrialkyl-arnmonio group, or (d) reacting compounds of the formula withreactive derivatives of the acid of the formula in which X is defined asabove and, if desired, converting the reaction products intophysiologically tolerable salts.

The reaction of starting materials mentioned under (a) is advantageouslycarried out in an inert solvent in the presence of a base such aspyridine or trimethylamine. But it is also possible to carry out process(a) with a molar excess of the aminopyrimidine to eliminate thehydrochloric acid formed during the reaction. The subsequent oxydationof the sulfenamides (n=) or sulfinamides (n=1) is effected in knownmanner, for example by treatment with hydrogen peroxyde, potassiumpermanganate or nitric acid.

The condensation of the acylaminoalkyl-benzenesulfonyl-guanidines withthe S-dicarbonyl compounds according to process (b) may be carried out,for example, by means of alkali alcoholate in alcohol. The ft-dicarbonylcompounds are used, to this effect, in free form or as functionalderivatives, for example, acetals; they may also be manufactured by oneprocedure without isolating the intermediate according to Vilsmeier fromaldehyde acetals or corresponding enamines, inorganic acid chloride anddialkyl formamide. When using corresponding substituted malonicdiesters, malonic ester aldehydes or the functional derivatives thereofinstead of the dicarbonyl compounds, the hydroxyl groups which are in 4-and/or 6-position of the pyrimidine ring must be replaced by halogenwith the aid of an inorganic acid halide, which may then be easilyexchanged by reduction, for example with zinc dust, against hydrogen.

The acylaminoalkylbenzenesulfonylguanidines used as starting compoundsmay be obtained, for example, by melting theacylaminoalkylbenzenesulfonamides with guanidine carbonate.

The condensation of the benzene guanidines with the pyrimidinederivatives according to (c) is preferably carried out in the presenceof a base such as potassium carbonate.

As starting compounds for the reaction according to (0) there areespecially suitable 2-halogenopyrimidines which are obtained by thereaction of the 2-hydroxy-pyrimidines with an excess ofphosphoroxy-chloride. Instead of the 2-halogenopyrimidines there mayalso be reacted the corresponding trialkylammonio-, nitroaminoorcyanamino-pyrimidines.

The acylation of the aminoalkylben'zenesulfonamidopyrimidines withquinoline-8-carboxylic acids according to (d) is carried out in knownmanner by reacting a reactive derivative, preferably an acid halide or amixed anhydride with the amino compound preferably in the presence of anacid binding agent.

The hypoglycemic action of the benzenesulfonamidopyrimidines can beascertained by administering them to normally fed rabbits in the form ofthe sodium salts in a dose of 10 mg./kg. of body weight and determiningthe blood sugar level according to the known method of Hagedorn-Jensenor by means of an auto-analyzer for a prolonged period of time.

The benzenesulfonamidopyrlmidines of the present invention arepreferably used for the manufacture of pharmaceutical preparationssuitable for oral administration and for the lowering of the blood sugarlevel in the treatment of diabetes mellitus and may be used as such orin the form of their salts or in the presence of substances which causesuch salt formation. For the formation of salts, there may be used, forexample, alkaline agents such as alkali metalor alkaline earth metalhydroxides, and alkali metal or alkaline earth metal carbonates orbicarbonates.

The present invention therefore also provides pharmaceuticalpreparations that have hypoglycemic action and are suitable for oraladministration in the treatment of diabetes mellitus, which preparationshave preferably the form of tablets and contain as the active ingredienta henzenesulfonamidopyrimidine of the invention or a salt thereof inadmixture or conjunction with pharmaceutically suitable carriers, suchas talc, starch, lactose, tragacanth and magnesium stearate.

A pharmaceutical preparation, for example, a tablet or a powder,containing the benzenesulfonamidopyrimidines of the invention or a saltthereof as the active substance, with or without one or more of theaforementioned carriers, is advantageously brought into a suitabledosage unit form. The dose chosen should comply 'with the activity ofthe benzenesulfonamidopyrimidine and with the desired effect.Advantageously, the dosage per unit amounts to about 1 to mg, preferably5 to 50 mg, but higher or lower dosage units may also be used, which,when required, are divided or multiplied prior to their administration.

The following Examples illustrate the invention:

EXAMPLE 1 4- (p-quinoline-8-carboxamido-ethyl)-N-(5-isobutyl2-pyrimidinyl)-benzene-sulfonamide 3.8 g. of2-amino-5-isobutyl-pyrimidine were suspended in 25 ml. of pyridine. 9.4g. of 4-(fl-quinoline-8-carboxamido-ethyl)-benzene-sulfochloride (M.P.14l-142 0., prepared from 4-18-quinoline-8-carboxamido-ethylbenzene andchlorosulfonic acid) were added while stirring and heated at 50 for 2hours. Subsequently, the pyridine was distilled off (to a large extent)under reduced pressure, the residue was dissolved in concentratedhydrochloric acid, clarified in charcoal and the solution was adjustedat pH 4 with concentrated ammonia. The 4-(p-quinoline-8-carboxamido-ethyl)-N-(5 isobutyl 2 pyrimidinyl)- benzene-sulfonamideprecipitated was recrystallized from nitromethane and melted at 177 to179.

In an analogous manner, there were obtained:

4-(B-quinoline-8-carboxamido-ethyl)-N-(5-ethyl-2-pyrimidinyl)-benzenesulfonamide,M.P. 182-184" (from nitromethane);

4- (B-quinoline-S-ca rb oxamidoethyl) -N-(S-propyl-Z-pyrimidinyl)-benzenesulfonamide, M.P. 166-168 (fromnitromethane);

4-(p-quinoline-8-carboxamido-ethyl)-N-(5-butyl-2-pyrimidinyl)-benzenesulfonamide,M.P. 18l-182 (from nitromethane);

4-(fi-quinoline-S-carboxamido-ethyl)-N-(5-ethoxy-2-pyrimidinyl)-benzenesulfonamide,M.P. 214-216 (from nitromethane);

4-(fl-quinoline-8-carboxamido-ethyl)-N-(S-phenyl-Z-pyrimidinyl)-benzenesulfonamide,M.P. 240242 (from water-DMSO);

from 4-(B-G-chloro-quinoline-S-carboxamido-ethyl)- benzenesulfochloride,M.P. 151-153;

4-(p-6-chloro-quinoline-S-carboxamido-ethyl)-N-(5-propyI-Z-pyrimidinyl)-benzenesulfonamide,M.P. 162- 163 (from nitromethane);

4-(fl-6-chloro-quinoline-8-carboxamido-ethyl)-N-(5-isobutyl-pyrimidinyl)-benzenesulfonamide, M.P. 153- (from nitromethane) 5 EXAMPLE 2 4-(fl-quinoline-8-carboxamido-ethyl)-N-(5-isobutoxy-2-pyrimidinyl)-benzene-sulfonamide 1 g. of triethyl-amine were added to1.73 g. of quinoline- 8-carboxylic acid in 30 ml. of acetone. 1.15 g. ofchloroformic acid ethyl ester were dropped to the solution while coolingwith ice, the whole was stirred again for a few minutes and the reactionmixture was slowly introduced in a cooled solution of4-(B-aminoethyl)-N-(5-isobutoxy-2- pyrimidinyl)-benzenesulfonamide,which was obtained by saponification of 4.23 g. of4-(B-ethoxy-carboxamido-ethyl)-N-(5isobutoxy-Z-pyrirnidinyl)-benzene-sulfonamide (M.P. 158) with 10% sodiumhydroxide solution and to which water, glacial acetic acid and acetonewere added. The whole was stirred again for 1 hour, water was added toit and it was acidified with acetic acid. The 4-(3-quinoline-8-carboxamido-ethyl)-N-(5 isobutoxy 2pyrimidinyl)-benzenesulfnamide was filtered off with suction andrecrystallized from ethanol. It melted at 188- 190".

In an analogous manner there were obtained from 4-fi-ethoxy-carboxamidoethyl -N--cyclohexyl-2-pyrimidinyl)-benzenesulfonamide, M.P. 167;

4-(B-6-chloro-quinoline-8-carboxamido)-N-(5-cyclohexyl-2-pyrimidinyl)-benzenesulfonamide,M.P. 218-220" (from ethanol-DMF);

4-(fi-6-bromo-quinoline-8-carboxamido)-N-(5-cyclohexyl-2-pyrimidinyl)-benzenesulfonamide,M.P. 217-219 (from ethanol-DMF) In an analogous manner, there wereobtained from 4- (fl-ethoxy-carboxamido-ethyl) -N-(5-isopropy1-4-methyl-2-pyrimidinyl)-benzenesulfonamide, M.P. 157;

4-( 3-6-chloro-quinoline-S-carboxamido)-N-(5-isopropy1-4-methyl-2-pyrimidinyl)-benzenesulfonamide, M.P. 218-220 (from ethanol);

4-(fi-fi-bromo-quinoline-8-carboxamido)-N-(5-isopropyl-4-methyl-2-pyrimidinyl)benzenesulfonamide, M.P. 227-229 (fromethanol-DMF).

In an analogous manner, there were obtained from4-(,8-ethoxy-carboxamido-ethyl)-N-(5-propyl-2-pyrimidinyl)-benzenesulfonamide,M.P. 162-463";

4- 3-6-bromo-quino1ine-8-carb oxamido -N- (S-propyl-2-pyrimidinyl)-benzene-sulfonamide, M.P. 203- 204 (from methanol-DMF);

from4-(B-ethoxy-carboxamido-ethyl)-N-(5-benzyl-2-pyrimidinyl)-benzenesulfonamide,M.P. 152-153";

4-(B-6-bromo-quinoline-8-carboxamido)-N-(5-benzyl-2-pyrimidinyl)-benzenesulfonamide, M.P. 186188 (from methanol-dioxane)In an analogous manner, there were obtained:

4- (fl-quinoline- 8-carb oxamido) -N- (5 -isopropyl-4-methyl-2-pyrimidinyl)-benzenesulfonamide, M.P. 194- 196 C.;4-(5-6-chloro-quinoline-S-carboxamido)-N-(5-isobutoxy-2-pyrimidinyl)-benzenesulfonamide, M.P. 153- 155 C.

EXAMPLE 34-(B-G-chloroquinoline-S-carboxamido-ethyl)-N-(5-ethylmercaptomethyl-Z-pyrimidinyl)-benzenesulfonamide1.9 g. of S-chloroquinoline-8-carboxylic acid and 10 ml. ofthionyl-chloride were refluxed for 3 hours. The excess ofthionyl-chloride was distilled ofi in vacuo and the residue wassuspended in 20 ml. of methylene chloride. This suspension was addedportionwise to the solution of 3.0 g. of4-(B-amino-ethyl)-N-(5-ethyl-mercaptomethyl-Z-pyrimidinyl)-benzenesulfonamidein 4.5 ml. 2 N sodium hydroxide solution and 20 m1. of water whilecooling with ice. The pH was adjusted at about 12 by gradually addingfurther sodium hydroxide solution. Stirring was continued for 1 hour,the pH being further maintained, if possible, at 12, then the solutionwas acidified with acetic acid and the methylene chloride was evaporatedby heating. The crude product precipitated was dissolved in very dilutesodium hydroxide solution under heat; while cooling, the sodium salt ofthe compound desired was crystallized out and was recrystallized fromabout 0.1 N sodium hydroxide solution by the addition of activecharcoal. The purified sodium salt was dissolved in hot water, the freefinal product was precipitated by acidification with acetic acid andrecrystallized from ethylene chloride after drying. The 4-(8-fi-chloroquinoline-8- carboxamido-ethyl)-N-(5-ethyl-mercapto-methyl 2pyrimidinyl)-benzenesulfonamide obtained melted at 178- 180 C.

The 4-(p-amino-ethyU-N-(5 ethyl-mercaptomethyl-2-pyrimidinyl)-benzenesulfonamide, M.P. 228-230 C. used as startingmaterial was prepared by alkaline hydrolysis of4-(fl-ethoxy-carboxamido-ethyl)-N-(5-ethyl-mercaptomethyl 2pyrimidinyl)-benzenesulfonamide, M.P. 156- 158 C.

In an analogous manner, the following compounds were obtained:

2- (6-chloroquinoline- 8-carboxamido) -N- S-isobutyl-Z-pyrimidinyl)-indane-5-sulfonamide, M.P. 24 8-250 C. (from isopropanol).

The 2-amino-N-(S-isobutyl-Z-pyrimidinyl) indane 5- sulfonamide, M.P.235240 0., used as starting material, was obtained by alkalinehydrolysis of Z-(ethoxy-carboxamido)-N-(5-isobutyl-2-pyrimidinyl)-indane 5 sulfonamide, M.P. 160l61 C.

2-(6-chloroquinoline-S-carboxamido)-N (5 isobutyl-2-pyrimidinyl)-1,2,3,4-tetrahydronaphthalene 7 sulfonamide, M.P. -121 C.(after recrystallization from isopropanol the substance was againdissolved in very dilute sodium hydroxide solution and was precipitatedwith dilute acetic acid).

The Z-amino-N-(S-isobutyl 2 pyrimidinyl) 1,2,3,4-tetrahydronaphthaline-7-sulfonamide, M.P. 244-245 0., used as startingmaterial, was prepared by alkaline hydrolysis of 2-(ethoxycarboxamido)-N(5 isobutyl 2- pyrimidinyl)-1,2,3,4 tetrahydronaphthaline 7 sulfonamide,M.P. 108-112 C.

We claim:

I 1. A sulfonamidopyrimidine of the formula R represents hydrogen or Rtogether with Y represents a bridge of 3 or 4 methylene groups,

R represents alkyl, cycloalkyl, cycloalkylalkyl, phenyl, bcnzyl, alkoxy,cycloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylmercapto,alkylmercaptoalkyl, the alky containing, in any case 1 to 4 carbon atomsand the cycoalkyl containing, in any case 5 to 8 carbon atoms,

R" represents hydrogen, alkyl of 1 to 4 carbon atoms, V

R and R together being able to represent a ring of from 3 to 5 methylenegroups. 2. A compound as defined in claim 1 wherein X is chlorinesubstituted in the 6-position, R and R" are hydrogen and R is isobutyl.

3. A compound as defined in claim 1 wherein X is References Citedchlorine substituted in the 6-position R and R" are UNITED STATESPATENTS h drogen and R is propyl.

4. A compound as defined in claim 1 wherein X, R and 3621026 11/1971Gutscht et a1 260256'5 R" are hydrogen and R is propyl. 5 RICHARD J.GALLAGHER, Primary Examiner 5. The compound of claim 1 which is4-(p-6-chloroquinoline-S-carboxamido ethyl) N (5 propyl 2-pyrimidinyl)-benzenesulfonamide. 260287 R; 424251

